In Vitro Release Test Methods for Drug Formulations for Parenteral Applications
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dx.doi.org/10.14227/DT250418P8 Reprinted with permission. Copyright 2018. The United States Pharmacopeial Convention. All rights reserved. In Vitro Release Test Methods for Drug Formulations for Parenteral Applications Vivian Gray,a Susan Cady,b David Curran,c James DeMuth,d Okponanabofa Eradiri,e Munir Hussain,f Johannes Krämer,g John Shabushnig,h Erika Stippler,i,j a V. A. Gray Consulting, Inc, Hockessin, DE. b Boehringer Ingelheim Animal Health, North Brunswick, NJ. c GlaxoSmithKline R&D, King of Prussia, PA. d University of Wisconsin, Madison, WI. e Food and Drug Administration, Silver Spring, MD.—The views presented in this article do not necessarily reflect those of the FDA. No official support or endorsement by the Food and Drug Administration is intended or should be inferred. f Bristol-Myers Squibb Company, New Brunswick, NJ. (Retired). g PHAST, Homburg, Germany. h Insight Pharma Consulting, LLC, Marshall, MI. i United States Pharmacopeia, Rockville, MD. j Correspondence should be addressed to: Desmond G Hunt, Principal Scientific Liaison, US Pharmacopeial Convention, 12601 Twinbrook Parkway, Rockville, MD 20852-1790; tel: +1.301.816.8341; email: [email protected] ABSTRACT In vitro drug release testing for parenteral drug formulations could benefit from more regulatory guidance and compendial information as this testing is a part of current expectations for drug product approval. This Stimuli article discusses in vitro drug release methods for those parenteral drug formulations that are not solutions and explores the challenges involved in using these methods for each formulation type. INTRODUCTION particulate matter, sterility, bacterial endotoxins, water his Stimuli article is the work of some members of the content, aluminum content, and content uniformity. General Chapters—Dosage Forms Subcommittee These tests are part of the compendial monograph [see Ton Parenterals. The Subcommittee is in agreement Injections and Implanted Drug Products 1 (2)]. with and endorses the content of this article. In vitro drug release testing for parenterals⟨ ⟩ that are non- Parenterally administered drugs include both injected solutions could benefit from more regulatory guidance and implanted drug formulations. While injections and compendial information. Method selection can are administered through the external boundary be challenging for many reasons, and each formulation tissue, implants are placed within the body to allow carries its own unique obstacles. The Dissolution direct administration of the drug substance(s) into the Procedure: Development and Validation 1092 (3) is an circulatory system or the local area. Injections exist as excellent reference for use when developing an in vitro solutions, suspensions, or suspensions with a modified- release test procedure. ⟨ ⟩ release component. Immediately prior to administration, the drug formulations may be reconstituted from sterile Each type of parenteral formulation is discussed in this Stimuli powders to form solutions, suspensions, and emulsions. article, including highlights of the formulation’s This category also includes drug-and-device combinations unique challenges. Examples of methods for current such as stents. formulations are provided; these examples were obtained from multiple sources, including but not limited to the FDA The definitions and descriptions of these dosage forms, Dissolution Method Database 4( ), workshop reports (5,6), as well as brief information about their composition and previous Pharmacopeial Forum Stimuli articles 7( , 8), and manufacturing processes, are found in Pharmaceutical the literature. For several parenteral drug formulations, Dosage Forms 1151 (1). procedures described in Dissolution 711 (9), Drug Release 724 (10), Mucosal Drug Products—Performance Tests In the case of parenteral⟨ ⟩ (non-solution) drug formulations, 1004 (11), or Semisolid Drug Products—Performance⟨ ⟩ the purpose of both the product quality tests and product Tests⟨ ⟩ 1724 (12) may be applicable. performance tests is to provide assurance of batch-to- ⟨ ⟩ batch quality, reproducibility, reliability, and performance. Because⟨ of ⟩the complex nature of some parenterals, the Product quality tests are performed to assess attributes in vitro drug release test methods will be applied on a such as assay, identification, impurities, foreign and case-by-case basis rather than using a one-size-fits-all 8 NOVEMBER 2018 www.dissolutiontech.com approach; however, the inclusion of general approaches The U.S. Food and Drug Administration (FDA) is providing and the presentation of options will be useful. Implanted guidance on in vitro performance testing of either parenteral drug formulations are long-acting dosage forms modified-release parenteral formulations or drug that provide continuous release of the drug substance(s), formulations containing nanomaterials 13( ). In vitro often for weeks, months, or years. For systemic delivery, drug release testing should be based on the compendial these dosage forms may be placed subcutaneously; for instruments described in 711 (9) and 724 (10). The local delivery, they may be placed in a specific region of most critical steps of in vitro testing are considered to the body. The in vitro test conditions should mimic specific be the insertion of the suspension⟨ ⟩ into the⟨ vessel⟩ or cell aspects of the intended physiological environment, and the phase separation after sampling. For filtration, such as the osmolarity, pH, or buffer capacity. Non-sink membrane filters are preferred. Cross-flow filtration conditions may be informative in some instances. has been shown to be advantageous (15). Compendial systems such as the basket or paddle and the flow-through The drug release test for some parenteral dosage forms cell apparatus allow the insertion of the suspension in a may require the use of modified compendial or non- bag, which often consists of dialysis membranes with a compendial equipment. For example, various volumes defined molecular cut-off. Alternatively, reversed dialysis of dissolution medium with or without agitation may techniques are applied with the suspension spread in the be appropriate. The use of dialysis membrane has been dissolution bulk medium. shown to be beneficial for some microsphere injectable formulations. Incubation methods have also been used. The use of in situ fiber optics combined with derivative Accelerated testing is a practical solution for quality spectroscopy has been shown to allow the quantification control testing; however, it should be justified as having of the dissolved drug substance in the presence of the relevance to “real time” release. nanoparticle-bound moiety of the active ingredient16 ( ). Although desirable, in vitro and in vivo correlations may The composition of the drug-release medium may be not be possible for modified-release parenteral dosage kept constant with regard to the physiological parameters forms due to the complexity of the release mechanisms for pH (pH 7.4) and osmotic pressure (285 mOsm/kg). and the lack of knowledge about in vivo release conditions. Because of the solubility of the drug substance and the requirement for an accelerated test, the addition of SUSPENSIONS surfactants [e.g., Tween 80 or sodium lauryl sulfate (SLS)] Although liposomes, microspheres, and nanosuspensions and/or organic solvents may be needed. Accelerated tests are considered suspensions, the discussion in this section are highly desirable. In addition to in vitro drug-release is limited to formulations of poorly water-soluble drug testing, data on the biological activity of the drug product substances or drug substances formulated with a release- may be needed for proper in vitro performance testing, controlling component, which is typically suspended in an particularly if the active ingredient is a biological, or in the aqueous medium. case of targeting and the route of administration. Nanosuspensions Liposomes In cases where suspensions exhibit, in principle, Liposomes are microvesicles composed of a lipid bilayer, particle sizes between 1 and 100 nm, they are called and/or a concentric series of multiple bilayers, separated nanosuspensions and have a tolerance extension up to by aqueous compartments. The compartments are 1000 nm (13). This suggests that dilution of the suspension formed by amphipathic molecules, such as phospholipids, prior to dissolution testing may alter the inherent drug that enclose a central aqueous compartment. Generally, release and/or dissolution characteristics significantly. liposomal formulations comprise the drug substance and lipids, as well as nonlipid and nonliposome inactive The most relevant parameters to modify for in vitro ingredients. In liposomal drug formulations, the performance testing are the content of organic solvents, drug substance is encapsulated within the aqueous the surfactants, and the pH of the media. The physiological compartment(s) or intercalated within the lipid bilayer(s). range for injectable dosage forms is around pH 7.4 and is narrower than that for oral dosage forms, even when The release of drugs from liposomal formulations can pathophysiological conditions are considered. In the case be modified by the presence of polyethylene glycol of osmotic systems, the osmolality of the in vitro drug (PEG) and/or cholesterol or other potential additives. release media composition requires attention. Diffusion It is pertinent to mention that the presence of PEG on mechanisms may prevail in the case of embedded or the surface of the liposomal carrier